Abstract This research challenges existing dogma for pre-emptive antibiotic use in preterm infants immediately after birth. Antibiotic use, especially when repeated, induces a perturbation (?dysbiosis?) in gut microbiota that may not recover to the basal state. A majority of preterm very low birthweight (VLBW) infants are exposed to antibiotics which have very poor evidence for such widespread use and are thus subjected to a potentially harmful course of antibiotics that provides no clear benefit. Our hypothesis is that early antibiotic use in preterm neonates has significant consequences on the developing intestinal microbiome, metabolome and host response, predisposing the neonate to various major morbidities. It is possible that the effect of this widespread antibiotic use outweighs the potential benefits. We propose a randomized trial of pre-emptive antibiotics versus no-pre-emptive antibiotics in preterms born at <33 weeks gestation. The purpose of this research is to evaluate the risks and benefits of current practice to determine optimal levels of antibiotic use that protects the babies from infection with minimal effect on the microbiome and subsequent adverse outcomes related to overuse of antibiotics. There are 2 specific aims: Aim 1. In a prospective, randomized pilot study, test the effects of pre-emptive postnatal antibiotics on the microbiome, metabolome and inflammatory responses in the neonate during the NICU course. We hypothesize that antibiotic use results in alterations in the microbial ecology of the intestinal microbiome that lasts well beyond discontinuance of antibiotic use and that this in turn results in altered fecal metabolic and inflammatory profiles that are associated with a higher incidence of adverse outcomes (Aim 2) while these infants are in the neonatal intensive care unit. Aim 2. In this same prospective, randomized pilot study, test the effects of pre-emptive postnatal antibiotics on adverse outcomes in the neonate while in the NICU. We hypothesize that higher antibiotic use will not be associated with decreased early onset sepsis and will be associated with increased adverse outcomes including necrotizing enterocolitis, late onset sepsis and mortality. At the end of this 2 year project, we will have effectively challenged existing dogma that nearly all preterm infants require at least a short course of intravenous antibiotics because of the risk of early onset sepsis. We will have a better understanding of the risks versus benefits of early pre-emptive antibiotic use in preterm infants. We will have a better understanding of the effects of antibiotics routinely given to preterm infants on the developing intestinal microbiome, metabolome and inflammatory status. It is anticipated that correlations to common morbidities such as late onset sepsis and necrotizing enterocolitis will be found. These will provide targets for future mechanistic based studies of causality. A greater justification and guidance for larger randomized trials may also result, which in turn will lead to major improvements in clinical care of preterm infants.